Abstract SY05-02: Understanding colorectal cancer as a stem cell hierarchy.

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Abstract The inner layer of the intestinal tube, the intestinal epithelium, is in a constant process of renewal. Hundreds of millions of terminally differentiated intestinal cells are replaced by new cells every day during the life of an adult organism. This tremendous regenerative power is ultimately sustained by a small population of intestinal stem cells. It is believed that alterations in the biology of human colon stem cells (CoSCs) account for the pathophysiology of various large-bowel disorders, including colorectal cancer (CRC). Yet, the identification of human CoSCs remains elusive. We have recently achieved for the first time the isolation of stem cells of the human colonic epithelium. Differential cell surface abundance of the receptor EPHB2 allows the purification of different cell types from human normal colon mucosa biopsies. Colon epithelial cells with highest EPHB2 levels exhibit the longest telomeres and express markers characteristic of intestinal stem cells. Using culturing conditions that recreate the intestinal stem cell niche, a substantial proportion of EPHB2-high cells can be expanded in vitro as an undifferentiated and multipotent population. Furthermore, we have also discovered that most human CRCs are constituted by cell populations with phenotypes similar to either CoSCs or intestinal differentiated cells organized into well-defined compartments. CoSC-like cells purified from primary CRCs generate tumors in immunodeficient mice with high efficiency and display both self-renewal and differentiation capacity. We demonstrated that CRC shares a common hierarchy with the intestinal mucosa and that the acquisition of an intestinal stem cell gene program is a central process during disease relapse after therapeutic intervention. Here I will present our latest data on the mechanisms employed by CRC stem cells to regenerate a new tumor at the metastatic site. We have discovered that metastasis relies on a tumor cell non-autonomous program expressed in the microenvironment. This stromal program confers a survival advantage to the disseminated CRC stem cells during the initial phase of metastasis. Citation Format: Eduard Batlle. Understanding colorectal cancer as a stem cell hierarchy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY05-02. doi:10.1158/1538-7445.AM2013-SY05-02